Regulation of NAD⁺ metabolism in aging and disease

More than a century after discovering NAD⁺, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD⁺ and NAD⁺ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD⁺ levels. Significantly reduced levels of NAD⁺ are also associated with aging, and enhancing NAD⁺ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD⁺ and enzymatic degradation of NAD⁺. Furthermore, the discovery of transporters and receptors involved in NAD⁺ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD⁺ and NAD⁺ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.